ABSTRACT Depression is the leading cause of disability worldwide. In Lusaka, Zambia, where our group has worked since 2001, as many as 1 in 5 pregnant and recently postpartum women meet criteria for perinatal depression (PND). This staggering rate coincides with another, equally staggering one: HIV prevalence among pregnant women in Lusaka exceeds 20%. As combination antiretroviral therapy (ART) has become available to an ever- growing number of pregnant women around the world, perinatal HIV transmission rates have plummeted. But, in order for infants of HIV-infected women to safely breastfeed, their mothers must adhere to their prescribed antiretroviral therapy. Many of the hallmark features of depression, such as sadness, fatigue, and withdrawal, work frustratingly against a woman's ability to adherence to her prescribed medication and keep her appointments. Treatment of depression in non-pregnant adults has been found in randomized trials to improve HIV outcomes. We hypothesize that treatment of PND in recently postpartum women will improve maternal health and protect the infant from breastfeeding HIV transmission. However, we are concerned about the feasibility of a full-scale efficacy trial, given the lack of knowledge in sub-Saharan Africa concerning depression and its treatment. In this application (AIM 1) we propose to study the feasibility of treating PND among HIV-infected women at two public sector facilities in Lusaka. The trial will screen women with an Edinburgh Postnatal Depression Scale (EPDS) and randomize those with clinically confirmed PND to either antidepressant medication (ADM); interpersonal psychotherapy (IPT); or the current standard of care (which includes access to HIV peer support groups). A total of 150 women will be enrolled and followed for 24 weeks. The primary objective of this research will be to demonstrate feasibility of a larger trial, which is expressed quantitatively in 4 objective measures: willingness to be screened for PND, prevalence of PND, willingness to participate in the trial, and retention of those enrolled. We will also measure preliminary efficacy of ADM and IPT in this population by comparing improvement in EPDS scores at study completion. In a set of concurrent, qualitative activities (AIM 2), we will seek a nuanced understanding of the personal, social, and structural barriers to participation in a depression study. We will invite women who decline enrollment in the trial to participate in semi-structured interviews (SSIs) to assess perceived risk of PND, attitudes regarding stigma associated with depression, and barriers to treatment. We will also invite women enrolled in the study to participate in longitudinal SSIs to explore similar factors regarding barriers, stigma, as well as perceptions and acceptability of treatment.